PROJECT SUMMARY/ABSTRACT The population-level impact of electronic nicotine delivery systems (?e-cigarettes?) will depend in large part on their effects on combustible tobacco cigarette smoking. Therefore, when using a population standard to make tobacco regulatory decisions, the impacts of e-cigarettes on cigarette smoking initiation, cessation, and relapse must all be considered. The National Academies of Sciences, Engineering, and Medicine (NASEM) concluded that there are key gaps in the literature regarding whether/how e-cigarette characteristics impact transitions to and from cigarette smoking. The proposed project will address these gaps by evaluating the independent effects of four e-cigarette design features that can be regulated by FDA action ? flavors, device type characteristics, nicotine content, and nicotine formulation ? on later cigarette smoking initiation, cessation, and relapse among youth and adult in the US. We will analyze data from the longitudinal Population Assessment of Tobacco and Health (PATH) Study, the US arm of the longitudinal International Tobacco Control (ITC) Youth Tobacco and E-cigarette Survey, and the US arm of the ITC Four Country Smoking and Vaping Survey. We will use generalized estimating equation regression analyses as well as propensity score matching techniques to increase statistical power and to statistically reduce potential confounding of associations by other factors. ? Aim 1 will examine e-cigarette use and cigarette initiation among nonsmoking youth and young adults. We will examine whether and how e-cigarette design features predict future cigarette smoking initiation, including progression to regular cigarette smoking. ? Aim 2 will examine e-cigarette use and cigarette cessation among youth and adult cigarette smokers. We will examine whether and how e-cigarette design features impact later cigarette smoking cessation, considering both the potential reach and effectiveness of design features. ? Aim 3 will examine e-cigarette use and cigarette relapse among adult former cigarette smokers. We will examine whether and how e-cigarette design features impact later cigarette smoking relapse. Addressing these aims together will provide balanced scientific evidence of the impact of e-cigarette design features on transitions both toward and away from cigarette smoking in the US ? the outcome upon which the net harm/benefit potential of e-cigarettes will ultimately hinge. These findings can directly inform FDA regulatory actions regarding product standards for e-cigarette flavors, device type characteristics, nicotine content, and nicotine formulation.